Abstract
BST-2/tetherin blocks the release of various enveloped viruses including HIV-1 with a “physical tethering” model. The detailed contribution of N-linked glycosylation to this model is controversial. Here, we confirmed that mutation of glycosylation sites exerted an effect of post-translational mis-trafficking, leading to an accumulation of BST-2 at intracellular CD63-positive vesicles. BST-2 with this phenotype potently inhibited the release of multivesicular body-targeted HIV-1 and hepatitis B virus, without affecting the co-localization of BST-2 with EEA1 and LAMP1. These results suggest that N-linked glycosylation of human BST-2 is dispensable for intracellular virion retention and imply that this recently discovered intracellular tethering function may be evolutionarily distinguished from the canonical antiviral function of BST-2 by tethering nascent virions at the cell surface.
Highlights
Humans and other mammals are equipped with endogenous cellular defense proteins as host restriction factors to provide resistance to infection, which must be overcome by viruses to facilitate their optimal replication
We primarily confirmed that the mutation of glycosylation sites in BST-2 exerted an effect of post-translational mis-trafficking, leading to its accumulation at intracellular CD63-positive vesicles and potently inhibited the release of multivesicular bodies (MVBs)-targeted HIV-1 and hepatitis B virus (HBV)
These results suggest that the recently discovered intracellular tethering function may be evolutionarily distinguished from the canonical antiviral function of BST-2 by tethering nascent virions at the cell surface
Summary
Humans and other mammals are equipped with endogenous cellular defense proteins as host restriction factors to provide resistance to infection, which must be overcome by viruses to facilitate their optimal replication. BST-2/tetherin is such an interferon-inducible antiviral glycoprotein [1,2], consisting of an N-terminal cytoplasmic tail (CT), a transmembrane (TM) domain, a coiled-coil extracellular domain and a glycosyl-phosphatidylinositol (GPI) anchor at the C-terminus [3]. BST-2 inhibits the release of various enveloped viruses [4] by tethering nascent virions at the cell surface, with its GPI anchors incorporated into the virion envelope and TM domains embedded in the host cell membrane to exert antiviral effects [5,6] via a “physical tethering” model that requires its structural domains and specific amino acid sites. BST-2 can be modified by multiple N-linked glycosylations at two conserved asparagine residues in its extracellular domain.
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